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The preparation method of the l-arginine salt of perindopril

A technology of arginine salt and arginine, applied in the field of preparation of L-arginine salt of perindopril, which can solve difficult processing problems

Active Publication Date: 2017-03-01
LES LAB SERVIER SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In fact, most of the trials carried out by the Applicant starting from perindopril and L-arginine to obtain the L-arginine salt of perindopril resulted in a product with a gel-like appearance which was extremely difficult to perform subsequently. processing

Method used

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  • The preparation method of the l-arginine salt of perindopril
  • The preparation method of the l-arginine salt of perindopril
  • The preparation method of the l-arginine salt of perindopril

Examples

Experimental program
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Effect test

Embodiment 1

[0045] Example 1 : L-arginine salt of perindopril - starting from perindopril (free acid) in a binary mixture of acetonitrile / DMSO 25 / 75 without seeding

[0046] Perindopril (12.5 g, 1 eq.) and L-arginine (5.32 g-0.9 eq) were suspended in a mixture of acetonitrile (20 g, d=0.787) and DMSO (61 g, d=1.100). The reaction mixture was heated at 50 °C overnight. The product was then isolated by filtration through a frit. Wash and dry the filter cake.

[0047] Perindopril arginine (14.5 g) was obtained with a yield of 79% relative to perindopril. The separated crystalline phase is the delta phase. The HPLC quality of the isolated product was greater than 99.0%.

[0048] The filtration rate of mother liquor is about 6000kg / h / m 2 .

[0049] The L-arginine salt of perindopril thus obtained was in the delta crystal form. This crystalline form has the following X-ray powder diffraction pattern, determined using a diffractometer with a copper counter-cathode and expressed as inter...

Embodiment 2

[0053] Example 2 : L-arginine salt of perindopril - start with perindopril (free acid) in a binary mixture of acetonitrile / DMSO 25 / 75, seeded

[0054] Perindopril (100 g, 1 eq.) and L-arginine (42.6 g, 0.9 eq.) were suspended in a mixture of acetonitrile (220 g, d=0.787) and dimethylsulfoxide (630 g, d=1.100) middle. The reaction mixture was heated at 70°C for 3 hours, seeded with 2% delta phase, then cooled to 40°C over 1 hour. The mixture was kept at 40°C while stirring for 18 hours, then cooled to 20°C over 1 hour. The product was then isolated by filtration. Wash and dry the filter cake.

[0055] Perindopril (L)-arginine (119 g) was obtained at a yield of 79% relative to perindopril. The HPLC quality of the isolated product was greater than 99.0%.

[0056] The filtration rate of mother liquor is about 6000kg / h / m 2 .

Embodiment 3

[0057] Example 3 : Starting from (2S, 3aS, 7aS)-2-carboxy-perhydroindole and N-[1-(S)-ethoxy-carbonyl-butyl]-(S)-alanine, by using N , General method of N'-carbonyl-diimidazole activation to generate perindopril (free acid)

[0058] N-[1-(S)-ethoxycarbonyl-butyl]-(S)-alanine (65g, 1eq.) and N,N'-carbonyldiimidazole (48g, 1eq.) were introduced, followed by acetonitrile (500g). The reaction mixture was then stirred for 3 hours at a temperature below +10°C.

[0059]The reaction mixture was poured into (2S, 3aS, 7aS)-2-carboxyperhydroindole (50 g, 1 eq.); an amount of fresh acetonitrile (80 g) was used to rinse the instrument.

[0060] The reaction mixture was then stirred at a temperature below +10°C for 5 hours and then clarified with a filter to obtain a clear solution.

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Abstract

Process for the preparation of the L-arginine salt of perindopril The present invention relates to a process for the preparation of the compound of formula (I) by the reaction between perindopril and L-arginine in a solvent system Carry out, described solvent system is selected from: the binary mixture of acetonitrile and dimethyl sulfoxide; The binary mixture of ethyl acetate and dimethyl sulfoxide; The ternary mixture of acetonitrile, dimethyl sulfoxide and toluene; Reaction temperature is at 10 -100°C, preferably 40-80°C, and then isolated by filtering the L-arginine salt thus obtained.

Description

technical field [0001] The present invention relates to the preparation method of the perindopril L-arginine salt of formula (I): [0002] Background technique [0003] Perindopril and its pharmaceutically acceptable salts, more specifically its L-arginine salt, have valuable pharmacological properties. [0004] Its main property is the inhibition of angiotensin I converting enzyme (or kininase II), which prevents, on the one hand, the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II (vasoconstrictor) and, on the other hand, prevents Bradykinin (vasodilator) is degraded to inactive peptides. [0005] Those two actions contribute to the beneficial effects of perindopril in cardiovascular disease, more specifically in arterial hypertension, heart failure and stable coronary disease. [0006] Perindopril, its preparation and its use in therapy are described in European patent specification EP0 049 658 . [0007] The L-arginine salt of perindop...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K1/02
CPCC07D209/42A61P43/00A61P9/00A61P9/04A61P9/10A61P9/12A61K31/404C07C277/08
Inventor J·里诺尔S·劳伦A·格勒尼耶S·马蒂厄
Owner LES LAB SERVIER SA
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